Pharmacology | Paramedicine 101

Does RSI Protect Against Aspiration of Stomach Contents

03/15/2012 by Rogue Medic 2 Comments

Also posted over at Rogue Medic (now at EMS Blogs).

One of the reasons we use RSI (Rapid Sequence Induction/Intubation) is to protect the airway from aspiration of stomach contents, blood, debris, and other things that might make their way into the lungs and make the patient’s already very bad day, very much worse.

Does RSI protect against aspiration of stomach contents?

We are presented with a patient who appears to need airway management.

You believe that tracheal intubation to isolate the respiratory from the gastrointestinal tract is considered to be the optimum method to prevent aspiration in at-risk patients. Limiting the time that the airway is unprotected during the induction of anesthesia is intuitively advisable and the practice of rapid sequence induction (RSI) with cricoid pressure is widely accepted as the standard of care in this setting.¹ ^[1]

When the word intuitively is used in a medical journal, that is a bad sign. The concerns about protecting the airway for anesthesia are minor concerns compared to those faced by EMS in the much less controlled prehospital environment.

As you contemplate the intervention, you wonder what evidence is available to measure the impact of RSI on the incidence of aspiration, how it should best be performed, and what is its risk-to-benefit profile.^[1]

Certainly, we should have considered this before beginning RSI, but this is a way of involving us in the care of a patient. I imagine Theodoric of York pausing during an intubation to ponder this. Naaaah!

Does this –

Image credit.

protect against this?

Image credit.

A search of the available research (2007) was performed and –

It was readily apparent that any conclusions addressing the primary question would be inadequately supported due to the limited number of studies, most of which were retrospective in nature. As well, the working definition of RSI used by researchers was variable and many of its component parts were of unproven or questionable merits.^[1]

This is not a review of whether EMS should use RSI, but of the evidence that RSI works in the ideal environment of the OR (Operating Room).

For the purpose of our review and discussion, we defined RSI as it would be conventionally carried out by practicing anesthesiologists. The technique evaluated includes preoxygenation, rapid administration of predetermined doses of both induction and paralytic drugs, concurrent application of cricoid pressure, avoidance of bag and mask ventilation, and direct laryngoscopy followed by tracheal intubation.^[1]

How many of us avoid the use of BVM (Bag Valve Mask) ventilation for preoxygenation?

If we have paralyzed the patient’s muscles to prevent stomach contents from being propelled out of the stomach, haven’t we also paralyzed the muscles that may prevent oxygen from entering the stomach?

If we are using BVM ventilation before giving paralytics, and some of that oxygen is forced into the stomach by BVM, aren’t we providing more pressure to propel stomach contents into the airway?

Can crichoid pressure decrease the amount of oxygen that enters the stomach by positive pressure ventilation?

However, a number of factors make it difficult to employ aspiration as the outcome variable in studies assessing the impact of RSI. Aspiration is rare and very large numbers of patients would need to be studied to assess the impact of RSI on its occurrence.^[1]

Is aspiration rare because RSI works to protect against aspiration?

Is aspiration rare regardless of RSI?

For practical reasons, surrogate outcomes, such as ease or success of intubation with RSI, are the most commonly reported, with successful tracheal intubation being the single most common outcome reported in clinical evaluations of RSI protocols.^[1]

Surrogate endpoints are great for the initial assessment of a treatment, but do not tell us what we need to know about whether what we are doing is actually helping patients, is of no benefit to patients, or is harmful to patients.

We need to do better than just following some old wives’ tales from a time when far less was known about patient care.

Further, many of the reports assessing RSI outcomes are simulations of RSI conducted in healthy elective populations who may not be representative of the cohorts of patients typically subjected to RSI.^[1]

In EMS, we should not be treating many healthy patients.

EMS is supposed to be providing not elective airway management, but necessary airway management.

Following our analysis of the literature it was apparent that there was no evidence available that would allow the following question to be answered: “Does RSI reduce either the incidence or the adverse consequences of aspiration during emergency airway management?” In fact, there is no study, randomized, controlled, blinded, or otherwise, that measures the impact of any intervention on the incidence of aspiration, nor is there likely to be a statistically meaningful study conducted on this issue.^[1]

This seems to prevent the study of RSI for aspiration prevention by anesthesiologists, but maybe it is still something that EMS can examine.

We are fortunate in that our patients tend to be much more nauseated by us. At least they tend to vomit on us, or around us, much more often than they do around others (maybe oncologists or gastroenterologists see more vomit than EMS).

Can we show that the attempts to prevent aspiration are more than just placebo?

How rare is aspiration in EMS?

How many patients might benefit from RSI to prevent aspiration?

Do we want to know if we are harming our patients?

Footnotes:

^[1] No evidence for decreased incidence of aspiration after rapid sequence induction.
Neilipovitz DT, Crosby ET.
Can J Anaesth. 2007 Sep;54(9):748-64. Review.
PMID: 17766743 [PubMed - indexed for MEDLINE]

Link to Abstract and Free Full Text PDF Download from Can J Anaesth

Assuming that the incidence of aspiration during emergency surgery is 0.15%,¹³ a strategy that would simply reduce the incidence by 50% would require a study of approximately 50,000 patients to confirm that benefit (one-tailed hypothesis for improved outcome, α = 0.05, β = 0.20). Thus, the strength of any recommendation favouring the use of RSI for the prevention of aspiration would be Grade D.^[1]

All we need to understand about the evidence grading system is that D is bad. The grades do not go any lower than D. D includes expert opinion, which is the least reliable evidence that should ever be considered. Expert opinion is what is behind one of the worst abuses of patients – the Standard Of Care – I’m doing it because everyone else is doing it, not because there is any good reason to believe it is good for the patient.

Science alone of all the subjects contains within itself the lesson of the danger of belief in the infallibility of the greatest teachers in the preceding generation … Learn from science that you must doubt the experts. As a matter of fact, I can also define science another way:

Science is the belief in the ignorance of experts. – Richard Feynman.

Filed Under: Airway Management, Heresy, Intubation, Pharmacology, Research, Rogue Medic

Intramuscular Midazolam for Seizures – Part VI

03/14/2012 by Rogue Medic 1 Comment

Also posted over at Rogue Medic (now at EMS Blogs).

How aggressive should we be in treating seizure patients based on this large double-blind, randomized, noninferiority trial comparing IM (IntraMuscular) midazolam (Versed) with IV (IntraVenous) lorazepam (Ativan)?

Which seizure patients should be treated with benzodiazepines?

Most patients stop seizing without any treatment and benzodiazepines can cause respiratory depression, so we need to be careful.

You can’t be too careful!

Right?

status epilepticus . . . occurs in approximately 6% of visits to the emergency department for seizures. . . . Although the term “prolonged” was previously used to refer to seizures lasting 30 minutes or longer, this interval has been shortened to 5 to 10 minutes in recent studies. This change occurred for several reasons. First, almost all convulsive seizures in adults cease in less than 5 minutes without treatment; seizures lasting longer than this are more likely to be self-sustained and to require intervention.^3,4 ^[1]

We used to be much more careful. We would wait half an hour before treating seizures out of a fear of making things worse. That fear caused us to make things worse by being too careful.

5 minutes seems to be the dividing line between seizures that will stop on their own and seizures that require treatment.

Second, the longer seizures persist, the harder they are to terminate pharmacologically.⁵ ^[1]

Being too careful resulted in higher doses of medication being given, because the dose that could have worked earlier in the seizure is no longer effective. The larger dose is also not effective. A different medication may also need to be added, even though it may not be effective, because we waited too long by being too careful!.

Delaying by more than 5 minutes increases the likelihood of not being able to stop the seizure with any medication. This is far worse than the potential side effects of giving a benzodiazepine to a patient who would otherwise have his seizure resolve spontaneously.

Third, outcome tends to correlate with seizure duration even after one controls for other factors. Mortality among patients who present in status epilepticus is 15 to 22%; among those who survive, functional ability will decline in 25% of cases.⁶ ^[1]

Benzodiazepine side effects should be easily managed, even by people with just advanced first aid training – protect the airway and make sure the patient is breathing. In the absence of adequate breathing, getting the patient to talk is most effective. If getting the patient to talk is unsuccessful, painful stimulus is indicated. If painful stimulus is unsuccessful, rescue breathing is indicated.

The effects of midazolam on the CNS are dependent on the dose administered, the route of administration, and the presence or absence of other medications. Onset time of sedative effects after IM administration in adults is 15 minutes, with peak sedation occurring 30 to 60 minutes following injection.^[2]

Midazolam given IM is not metabolized as quickly as when given IV, but midazolam should still be metabolized more quickly than IV lorazepam (Ativan). Unfortunately, the label does not include information about the time to return to being alert following IM midazolam, so I can only make this apples and oranges comparison. When I have given midazolam IV, I have had to give more midazolam before arriving at the hospital (after I had given a total dose that was successful) or more sedation has had to be given the hospital (after I had given a total dose that was successful). I have never seen IV lorazepam metabolized that quickly. So midazolam is metabolized much more quickly IV, than lorazepam is metabolized IV. Unfortunately, I could not find more appropriate information to compare the metabolism of IM midazolam and IV lorazepam.

The intended effects of the recommended adult dose of ATIVAN Injection usually last 6 to 8 hours.^[3]

Image credit.

This study does show that the patients receiving IM midazolam did not end up hospitalized as often, which may be due to more rapid metabolism of IM midazolam.

the proportion of subjects admitted was significantly lower (and the proportion discharged from the emergency department was significantly higher) in the intramuscular group than in the intravenous group (P=0.01).^[4]

What is needed is a good study comparing buccal midazolam, IN (IntraNasal) midazolam, and IM midazolam to find out which works best. Perhaps a rectal diazepam group could be included to put another nail in that coffin, but rectal diazepam has the one thing going for it that no amount of evidence seems to be able to overcome – tradition. We need to stop killing our patients with tradition.

Multiple studies have shown that nasal or buccal midazolam stops seizures faster than rectal or intravenous diazepam¹³ and is absorbed faster than intramuscular midazolam.^{13 – 15} ^[1]

Buccal or IN midazolam stops seizures faster than IV or rectal diazepam, but is only absorbed faster than IM midazolam?

Footnotes:

^[1] Intramuscular versus intravenous benzodiazepines for prehospital treatment of status epilepticus.
Hirsch LJ.
N Engl J Med. 2012 Feb 16;366(7):659-60. No abstract available.
PMID: 22335744 [PubMed - in process]

^[2] MIDAZOLAM HYDROCHLORIDE injection, solution
[Hospira, Inc.]
DailyMed
FDA Label

^[3] ATIVAN (lorazepam) injection, solution
[Baxter Healthcare Corporation]
DailyMed
FDA Label

^[4] Intramuscular versus intravenous therapy for prehospital status epilepticus.
Silbergleit R, Durkalski V, Lowenstein D, Conwit R, Pancioli A, Palesch Y, Barsan W; NETT Investigators.
N Engl J Med. 2012 Feb 16;366(7):591-600.
PMID: 22335736 [PubMed - in process]

Filed Under: Heresy, Pharmacology, Research, Rogue Medic

Intramuscular Midazolam for Seizures – Part V

03/13/2012 by Rogue Medic 1 Comment

Also posted over at Rogue Medic (now at EMS Blogs).

How should this large double-blind, randomized, noninferiority trial comparing IM (IntraMuscular) midazolam (Versed) with IV (IntraVenous) lorazepam (Ativan) affect the way we treat patients with seizures?

Click on image to make it larger.

21.3% of patients had their seizures stop before they could be given IV lorazepam, while none of the IM midazolam patients had seizures stop before being given medication.

Does that provide a bias toward improved outcomes with IM midazolam?

Study Outcomes
The primary outcome was termination of seizures before arrival in the emergency department without the need for the paramedics to provide rescue therapy.^[1]

Seizures were absent without rescue therapy on arrival in the emergency department in 329 of 448 subjects assigned to active treatment with intramuscular midazolam (73.4%) and in 282 of 445 assigned to active treatment with intravenous lorazepam (63.4%) (difference, 10 percentage points; 95% confidence interval [CI], 4.0 to 16.1; P<0.001 for noninferiority and P<0.001 for superiority) (Fig. 2).^[1]

The patients who had seizures stop without any lorazepam are included in those considered successfully treated.

This is appropriate, since we can expect a similar rate of spontaneous resolution among the patients receiving IM midazolam. The only difference is that those patients will have received the midazolam so quickly that the seizure will not yet have stopped.

Status epilepticus was terminated by the time of arrival at the emergency department in 59.1 percent of patients given lorazepam, 42.6 percent of patients given diazepam, and 21.1 percent of patients given placebo (P=0.001)^[2]

Is this a reason to avoid/delay administration of IM midazolam?

No.

The greater risk appears to be to the patients with continuing seizures. The primary benefit of IM midazolam is the rapid administration.

There is no evidence of any harm to the patients who would have their seizures stop without midazolam. There is evidence of harm from delaying/avoiding treatment. Most seizures will stop prior to the arrival of EMS. Delays in treatment should probably only be for those known to have self-limiting seizures and EMS is at the patient’s side in less than 5 minutes.

An out-of-hospital complication (hypotension, cardiac dysrhythmia, or respiratory intervention) occurred in 7 (10.6 percent) of the patients treated with lorazepam, 7 (10.3 percent) of the patients treated with diazepam, and 16 (22.5 percent) of the patients given placebo (P=0.08). The most common complication was a change in respiratory status requiring ventilation assistance by bag valve-mask or an attempt at intubation (7 patients given lorazepam, 6 given diazepam, and 11 given placebo).^[2]

Those who did not receive benzodiazepines did not do as well as those who did receive benzodiazepines – this includes the most worrisome side effect of benzodiazepines – respiratory compromise. We are not improving outcomes by delaying care or by using low doses.

Among subjects admitted to the hospital, the lengths of stay in the intensive care unit and in the hospital did not differ significantly between the groups, but the proportion of subjects admitted was significantly lower (and the proportion discharged from the emergency department was significantly higher) in the intramuscular group than in the intravenous group (P=0.01).^[1]

If there is no IV already in place, is there much reason to not use IM midazolam for active seizures?

No.

Our data are consistent with the finding that endotracheal intubation is more commonly a sequela of continued seizures than it is an adverse effect of sedation from benzodiazepines.¹¹ ^[1]

High dose benzodiazepines appear to be more likely to prevent intubation, than to result in intubation. This is something that many medical directors do not seem to have considered.

See also Part I, Part II, Part III, and Part IV.

Footnotes:

^[1] Intramuscular versus intravenous therapy for prehospital status epilepticus.
Silbergleit R, Durkalski V, Lowenstein D, Conwit R, Pancioli A, Palesch Y, Barsan W; NETT Investigators.
N Engl J Med. 2012 Feb 16;366(7):591-600.
PMID: 22335736 [PubMed - in process]

^[2] A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus.
Alldredge BK, Gelb AM, Isaacs SM, Corry MD, Allen F, Ulrich S, Gottwald MD, O’Neil N, Neuhaus JM, Segal MR, Lowenstein DH.
N Engl J Med. 2001 Aug 30;345(9):631-7. Erratum in: N Engl J Med 2001 Dec 20;345(25):1860.
PMID: 11547716 [PubMed - indexed for MEDLINE]

Free Full Text from N Engl J Med. with link to PDF Download

Filed Under: Heresy, Pharmacology, Research, Rogue Medic

Intramuscular Midazolam for Seizures – Part IV

03/09/2012 by Rogue Medic 1 Comment

Also posted over at Rogue Medic (now at EMS Blogs).

What does this study mean for the treatment of patients who are having seizures?

The median time to administration of active treatment was significantly shorter by the intramuscular route than by the intravenous route (1.2 vs. 4.8 minutes), but the onset of action (i.e., termination of convulsions) occurred sooner after intravenous administration than after intramuscular administration (1.6 vs. 3.3 minutes).^[1]

Click on images to make them larger.

The good news for fans of IV (IntraVenous) drugs for seizures is that giving IV lorazepam at the same time as giving IM (IntraMuscular) midazolam will result in faster termination of seizures.

If an IV is already in place, the average time for the IV lorazepam to stop the seizure is about 1.6 minutes after the lorazepam is pushed into the IV line.

The average time for the IM midazolam to stop the seizure is about 3.3 minutes after the midazolam is injected into the muscle.

If an IV is already in place, IV lorazepam should be significantly faster.

Would IV midazolam also work faster than IM midazolam?

Probably, but that was not demonstrated in this study. My preference is to give IV midazolam, rather than IV lorazepam, because the midazolam will wear off more quickly.

I am initially much more interested in stopping the seizure, than in the side effects that might be present as a result of aggressive dosing of benzodiazepine.

After the seizure, I want any side effects to stop as quickly as possible. Midazolam is going to be metabolized much more quickly than lorazepam. In the hospital, the continuing treatment of the patient will be in the hands of the emergency physician who will have a much broader selection of medications available to treat against further seizures.

Benzodiazepines appear to be the best emergency treatment for seizures, but they may not be good for longer term treatment of the same seizures.

The problem is that EMS and ED (Emergency Department) patients rarely have an IV in place when seizures begin and it is not easy to start an IV on a patient while the patient is seizing.

Image credit.

If an IV is NOT in place, then the delay in giving the medication is both dramatic and significant enough to completely eliminate the difference in absorption that favors giving IV medication.

With average times of 1.2 minutes from opening the medication box to injecting the medication IM and 4.8 minutes from opening the medication box to injecting the IV medication, the difference is 3.6 minutes.

The IV lorazepam works 1.7 minutes faster, but it takes 3.6 minutes longer before the IV lorazepam can be given, on average.

That difference means that the IM midazolam stops the seizure 1.9 minutes faster than the IV lorazepam.

The average total time to termination of seizure after opening the medication container was 6.4 minutes with IV lorazepam.

The average total time to termination of seizure after opening the medication container was 4.5 minutes with IM midazolam.

After 4.5 minutes, the medic is still working on starting the IV, but the seizure has already stopped in the IM midazolam group.

This should not be a difficult decision.

See also Part I, Part II, and Part III. To be continued in Part V.

Footnotes:

Filed Under: Heresy, Pharmacology, Research, Rogue Medic

Intramuscular Midazolam for Seizures – Part III

02/20/2012 by Rogue Medic 1 Comment

Also posted over at Rogue Medic (now at EMS Blogs).

I have already pointed out my disappointment with the references of this large double-blind, randomized, noninferiority trial comparing IM (IntraMuscular) midazolam (Versed) with IV (IntraVenous) lorazepam (Ativan). One of those criticisms appears to be just due to a typographical error. The footnote in the text was ¹¹, but the footnote should have been ¹.

The relationships among benzodiazepine dose, respiratory depression, and subsequent need for endotracheal intubation are poorly characterized, but higher doses of benzodiazepines may actually reduce the number of airway interventions. Our data are consistent with the finding that endotracheal intubation is more commonly a sequela of continued seizures than it is an adverse effect of sedation from benzodiazepines.¹¹ ^[1]

Here is some of the information from footnote ¹. One interesting aspect of this double-blind study is that there is a placebo group. Patients received 2 mg IV lorazepam, 5 mg IV diazepam (Valium), or IV placebo. Treatment could be repeated one time if seizures continued for more than 4 minutes or if seizures recurred.

Cardiorespiratory complications before arrival at the hospital and at the time of transfer were important secondary outcomes that relate to the safety of out-of-hospital therapy with intravenous benzodiazepines. Despite concern regarding the adverse effects of these agents, we found a trend toward lower rates of out-of-hospital complications (primarily respiratory compromise) in the active-treatment groups than in the placebo group. This suggests that respiratory complications associated with prolonged seizures may be more pronounced than those caused by intravenous lorazepam and diazepam given at relatively low doses.^[2]

The doses are low. The lorazepam dose is only half of the 4 mg used in the IV lorazepam vs. IM midazolam study.

The doses of midazolam and lorazepam used in this trial are consistent with the most effective doses for the treatment of status epilepticus that are reported in the literature.^9,10 Although these initial doses are higher than the ones used by many EMS systems and emergency physicians, they are the same as those approved for this indication and are in line with those used by epileptologists.^[1]

Is there added safety from the lower doses?

The epilepsy specialists and the FDA (Food and Drug Administration) do not recommend lower doses.

Were the low doses effective?

2 mg midazolam?

Does anyone really expect such a small dose to make a difference?

Despite the beneficial outcomes associated with intravenous lorazepam and diazepam, 41 to 57 percent of patients who received active treatment were still in status epilepticus at the time of arrival at the emergency department. These patients were more than twice as likely to require intensive medical care as those whose seizures ended outside the hospital. Differences in the causes of the episodes of status epilepticus are unlikely to account for this difference. These observations, coupled with the favorable risk–benefit profile associated with lorazepam and diazepam in this trial, suggest that higher doses should be studied to define the optimal therapy for patients with out-of-hospital status epilepticus.^[2]

An editorial refers to the study just published^[1] and to the benzodiazepine vs. placebo study.^[2] Describing the complications in the placebo study, the author wrote –

Successful termination was much more common in the two groups that received benzodiazepines (59% with lorazepam, 43% with diazepam, and 21% with placebo). Since respiratory distress was twice as common in the group given placebo as in either of the groups given a benzodiazepine, the best way to avoid the need for intubation is to stop seizure activity.^[3]

This presents an interesting conundrum. Doses of benzodiazepines (midazolam, lorazepam, diazepam, . . .) are often limited, due to a fear of causing respiratory complications.

When treating seizures, higher doses of benzodiazepines may actually protect patients from respiratory complications.

With a fatality rate around 10%, seizures are certainly not benign.

Maybe early treatment with high dose benzodiazepines can significantly decrease that fatality rate.

Finally, relatively few out-of-hospital interventions have been evaluated in randomized controlled trials,¹⁶ and when they have been evaluated carefully, therapies with intuitive appeal have often been found either to lack benefit or to cause harm to patients.^17-20 ^[2]

The irony is that we may be doing the opposite by limiting doses of benzodiazepines to less than what is recommended by the FDA.

What do you think?

See also Part I and Part II. To be continued in Part IV.

Footnotes:

Free Full Text from N Engl J Med. with link to PDF Download

^[3] Intramuscular versus intravenous benzodiazepines for prehospital treatment of status epilepticus.
Hirsch LJ.
N Engl J Med. 2012 Feb 16;366(7):659-60. No abstract available.
PMID: 22335744 [PubMed - in process]

Filed Under: Heresy, Pharmacology, Research, Risk Management, Rogue Medic

Intramuscular Midazolam for Seizures – Part II

02/19/2012 by Rogue Medic 1 Comment

Also posted over at Rogue Medic (now at EMS Blogs).

While there have been studies comparing IM (IntraMuscular) midazolam (Versed) with IV (IntraVenous) anti-epileptic medications, this is a large study that compares IM midazolam with the best IV anti-epileptic medication in a double-blind, randomized, noninferiority trial.

All adults and those children with an estimated body weight of more than 40 kg received either 10 mg of intramuscular midazolam followed by intravenous placebo or intramuscular placebo followed by 4 mg of intravenous lorazepam.^[1]

For the study, there were two different doses for the auto-injector (similar to an EpiPen auto-injector). The doses were not small.

Midazolam for seizures is an off-label use both when given IM and when given IV.^[2]

The lorazepam IV doses in the study are according to the FDA label –

For the treatment of status epilepticus, the usual recommended dose of Lorazepam Injection is 4 mg given slowly (2 mg/min) for patients 18 years and older. If seizures cease, no additional Lorazepam Injection is required. If seizures continue or recur after a 10- to 15- minute observation period, an additional 4 mg intravenous dose may be slowly administered.^[3]

Unfortunately, my protocols only permit 1/4 or 1/2 the dose of lorazepam for seizures, which may be repeated every 5 minutes up to a maximum of one full dose recommended as the initial dose by the FDA.^[4] There is no adult IM use of midazolam.

There is often a concern about carefully adjusting pediatric doses. How did they handle that in this study?

In children with an estimated weight of 13 to 40 kg, the active treatment was 5 mg of intramuscular midazolam or 2 mg of intravenous lorazepam.^[1]

But such high doses will lead to deadly outcomes

Except that this excuse to give low doses is not supported by the authors of this study.

The relationships among benzodiazepine dose, respiratory depression, and subsequent need for endotracheal intubation are poorly characterized, but higher doses of benzodiazepines may actually reduce the number of airway interventions. Our data are consistent with the finding that endotracheal intubation is more commonly a sequela of continued seizures than it is an adverse effect of sedation from benzodiazepines.¹¹^[1]

That is a very interesting comment. The authors believe that intubations are increased by not controlling the seizure, rather than by giving large doses of a benzodiazepine. Unfortunately. I did not see anything to support that statement in the paper they cited as footnote 11.^[5]

See also Part I. To be continued in Part III, and Part IV.

Footnotes:

^[2] MIDAZOLAM HYDROCHLORIDE injection, solution
[Hospira, Inc.]
DailyMed
NLM
FDA label

I checked all of the injectable formulations of midazolam. They are the same. None include recommended dosing for seizures, but all include warnings about midazolam possibly causing seizures.

^[3] Lorazepam (lorazepam) Injection, Solution
[Baxter Healthcare Corporation]
DailyMed
NLM
FDA label

^[4] Seizure
Pennsylvania Statewide Advanced Life Support Protocols
7007 – ALS – Adult/Peds
Page 100/128
Free Full Text PDF of All ALS Protocols

Titrate until seizure stops.

Split the dose in half. Repeat the dose in 5 minutes.

There is no option for adult IM dosing.

^[5] A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children.
Chamberlain JM, Altieri MA, Futterman C, Young GM, Ochsenschlager DW, Waisman Y.
Pediatr Emerg Care. 1997 Apr;13(2):92-4.
PMID: 9127414 [PubMed - indexed for MEDLINE]

Filed Under: Heresy, Pharmacology, Research, Rogue Medic

Nifekalant versus lidocaine for in-hospital shock-resistant ventricular fibrillation or tachycardia

01/04/2012 by Rogue Medic 1 Comment

Also posted over at Rogue Medic (now at EMS Blogs) and at Research Blogging. Go check out the excellent material at these sites.

Also posted over at Rogue Medic (now at EMS Blogs).

This is an interesting study for several reasons. One is the ability of the authors to act out parts of Through the Looking-Glass.^[1] VF and VT are Ventricular Tachycardia and Ventricular Fibrillation.

If life-threatening VF or VT persists despite repeated deﬁbrillation shocks, an additional antiarrhythmic drug is required.^[2]

The next paragraph points out that there is no requirement according to ACLS.

The American Heart Association guideline for advanced cardiac life support (ACLS) states that when VF/pulseless VT persists after two to three shocks plus CPR and administration of a vasopressor, the physician should consider administering an anti-arrhythmic such as amiodarone, and lidocaine may be considered if amiodarone is unavailable.¹ ^[2]

Believing that should consider administering is the same as an additional antiarrhythmic drug is required requires the same lack of illogic as used by the Queen, when instructing Alice to practice believing impossible things.

Then there are the obvious questions. Why compare nikefelant with lidocaine? Why not compare nikefelant with amiodarone? Why not compare nikefelant with an antiarrhythmic that is more effective than amiodarone – procainamide, sotalol, or ajmaline?

Lidocaine is probably used because the IRB (Institutional Review Board) would consider it unethical to have a placebo group. Lidocaine is the placebo, but with less safety than the placebo.

It was by comparing amiodarone with lidocaine that ACLS ended up including amiodarone for VT/VF cardiac arrests. That was a huge boon for Wyeth. We were told that the improved survival to admission was important. We were told that survival studies – the only studies that matter in resuscitation – were being done. We have had only silence since then.

~~We should conclude that amiodarone does not improve survival.~~

No. That is not the right conclusion. If amiodarone produced survival as good as placebo, then that study would have been published and used to justify giving amiodarone. At least we are doing something! That is what people want to believe in.

The only reasonable conclusion is that Wyeth did not publish the results because the survival in the amiodarone group was significantly worse than in the placebo group, or Wyeth stopped the study early, because it was trending toward statistically significant harm from amiodarone.

If the study never reaches statistical significance, they can always rely on there being no proof of harm. That is what we have now and there are plenty of people claiming that no proof of harm means obvious benefit.

Original cartoon

We have a lot of ignorant/willfully ignorant people encouraging us to just give drugs because we cannot prove that these drugs are harmful. We cannot provide evidence that the drugs are harmful, because it is almost impossible to approve a placebo-controlled study to find out. The IRBs claim that it would be unethical to deprive patients of the Standard Of Care, no matter how harmful that Standard Of Care may be. If the IRBs approve a study, the politicians oppose the study.

There were some interesting differences between the lidocaine and nukefalant groups.

The number of shocks before study-drug administration did not differ between the two arms, although epinephrine use before study-drug administration was signiﬁcantly higher in the lidocaine arm (Table 2).^[2]

Epinephrine use
Nikefalant 6/27 – 22.2%
Lidocaine 20/28 – 71.4%
With a p value of <0.001

According to ACLS, an antiarrhythmic should not be considered until after a pressor is considered.

Patients with nifekalant were more likely to have ROSC compared with patients with lidocaine (Table 3). However, there was no difference in 1-month survival or survival to hospital discharge between the nifekalant arm and the lidocaine arm.^[2]

The overall outcome, such as survival rate, of patients with shock-resistant VF or VT is poor regardless of the pharmacological intervention. Nevertheless, termination of VF or VT and recovery of ROSC by nifekalant is important in the initial stage of resuscitation, because we cannot rescue the patients unless VF or VT is converted.^[2]

They assume that the VF/VT will not be converted without a drug.

They assume that converting more VF/VT will lead to more survival even though there continues to be absolutely no evidence to support this hope.

It is reasonable to assume that the short-term thrill of conversion of VF/VT to a better rhythm comes at the expense of long-term harm to the patient.

We need to stop falling for feel good endpoints that encourage us to harm our patients.

If others are NOT helping their patients with these drugs, we want to be NOT helping our patients, too!

Footnotes:

^[1] Through the Looking-Glass
by Lewis Carroll
The Millennium Fulcrum Edition 1.7
CHAPTER V. Wool and Water

‘I can’t believe THAT!’ said Alice.

‘Can’t you?’ the Queen said in a pitying tone. ‘Try again: draw a long breath, and shut your eyes.’

Alice laughed. ‘There’s no use trying,’ she said: ‘one CAN’T believe impossible things.’

‘I daresay you haven’t had much practice,’ said the Queen. ‘When I was your age, I always did it for half-an-hour a day. Why, sometimes I’ve believed as many as six impossible things before breakfast.

^[2] Nifekalant versus lidocaine for in-hospital shock-resistant ventricular fibrillation or tachycardia.
Shiga T, Tanaka K, Kato R, Amino M, Matsudo Y, Honda T, Sagara K, Takahashi A, Katoh T, Urashima M, Ogawa S, Takano T, Kasanuki H; Refractory VT/VF, Prospective Evaluation to Differentiate Lidocaine Efficacy from Nifekalant (RELIEF) Study Investigators.
Resuscitation. 2010 Jan;81(1):47-52. Epub 2009 Nov 13.
PMID: 19913983 [PubMed - indexed for MEDLINE]

^[3] Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial
Jacobs IG, Finn JC, Jelinek GA, Oxer HF, Thompson PL.
Resuscitation. 2011 Sep;82(9):1138-43. Epub 2011 Jul 2.
PMID: 21745533 [PubMed - in process]

Free Full Text PDF Download of In Press Uncorrected Proof from xa.yming.com

This study was designed as a multicentre trial involving five ambulance services in Australia and New Zealand and was accordingly powered to detect clinically important treatment effects. Despite having obtained approvals for the study from Institutional Ethics Committees, Crown Law and Guardianship Boards, the concerns of being involved in a trial in which the unproven “standard of care” was being withheld prevented four of the five ambulance services from participating.

In addition adverse press reports questioning the ethics of conducting this trial, which subsequently led to the involvement of politicians, further heightened these concerns. Despite the clearly demonstrated existence of clinical equipoise for adrenaline in cardiac arrest it remained impossible to change the decision not to participate.

Filed Under: AHA Guidelines, Cardiac Arrest, Heresy, Pharmacology, Research, Rogue Medic

Intraosseous Versus Intravenous Vascular Access During Out-of- Hospital Cardiac Arrest – A Randomized Controlled Trial

12/15/2011 by Rogue Medic 1 Comment

Also posted over at Rogue Medic (now at EMS Blogs).

For treatment of medical cardiac arrest patients, which is better – IO (IntraOsseous) or IV (IntraVenous) access for medication administration?

Since no medications have ever been demonstrated to improve survival from cardiac arrest (only chest compressions and defibrillation have), the most important consideration will be what method results in the least interruption of compressions and the least interference with defibrillation.

All patients eligible for inclusion in this study had their ﬁrst attempt at vascular access randomized to one of 3 locations: proximal tibial intraosseous, proximal humeral intraosseous, or peripheral intravenous. The proximal tibial insertion site was located medial to the tibial tuberosity, or just below the patella along the ﬂat aspect of the tibia. The proximal humerus insertion site was deﬁned as the greater tubercle of the anterior humeral head 1 cm proximal to the surgical neck of the humerus. Peripheral intravenous catheter placement could occur at any accessible peripheral vein but preferably at the antecubital fossa; the external jugular vein was not an option provided for catheterization.^[1]

Proximal tibial access points.

Proximal humeral access point.
Images credit.

Does this hurt? No. The patients are unresponsive and pulseless (dead), but even live patients and EMS personnel (who have tried this on themselves) report very little pain.

Overall success took into account a failure to maintain initial vascular access during the course of resuscitation, which included needle dislodgement or the inability to successfully administer medications or ﬂuid at any time during the resuscitation.^[1]

Those would interfere with the one claimed benefit – ability to deliver medication.

There was no difference in time to success for either of the intraosseous routes compared with the peripheral intravenous route.^[1]

Click on images to make them larger.

The time to success is interesting. The times for the humeral site are similar to the tibial IO and the IV for placement and first drug administration – at least at the low end of the IQRs (InterQuartile Ranges). The problem is that the upper end of the IQRs is much longer than for the other methods. This is in part due to the low number of patients, which is partially explained by the 13 protocol violations – all in favor of the tibial IO site. The lack of familiarity of paramedics probably also contributes, resulting in much longer times for some of the paramedics.

Finally, there were 13 protocol violations that favored the tibial intraosseous route, which may have been an indicator of bias among paramedics for that route and therefore could have resulted in confounding of the study results.^[1]

It may be that this group of paramedics was much more comfortable with the tibial IO, than with the humeral IO and this led to a greater likelihood of coming up with excuses for protocol violations. This may also have led to the performance differences. I have seen similar differences with the introduction of a new type of IV catheter to some services. There can be a lot of conscious and unconscious resistance to the new method, but after some familiarity develops, things tend to return to normal.

In the literature, intraosseous needle insertions have been linked to local wound infections, osteomyelitis, fat emboli, and compartment syndrome.^18-20 During this study, there was no mechanism in place for EMS or hospital personnel to report complications in the use of the intraosseous device.^[1]

That would be good to know, but this was not one of the goals of the study.

The average weight of patients in the humeral intraosseous group was greater than that of individuals in either of the other 2 arms of the study. This increased weight may have been associated with a difﬁculty in obtaining or maintaining vascular access.^[1]

Weight can be a problem for any method of IV/IO access, so this is a very important limitation.

Weight – mean (SD)

Overall – 97.3 kg (2.7)

Humeral IO – 103.9 kg (6.5)

IV – 97.7 kg (3.8)

Tibial IO – 91.5 kg (3.9)

An average weight of 228.6 pounds (103.9 kg) in the humeral IO group, but only 201.3 pounds (91.5 kg) in the tibial IO group? 27.3 pounds difference (13.8% difference).

That strongly suggests a problem.

The proximal humerus can also prove tenuous during cardiac arrest because it is centered near the upper torso, where resuscitation efforts are occurring, including airway management, ongoing chest compressions, and rescuer interchange. The constant activity creates a tremendous amount of movement and further increases the risk of unintentional needle dislodgement, which was veriﬁed during the debrieﬁng session after each out-of-hospital cardiac arrest, with paramedics frequently citing entanglement of the humeral intraosseous line, leading to dislodgement.^[1]

The peripheral intravenous site is the most commonly used vascular access by all health care providers, yet it proved successful in less than 50% of cases in this study.^[1]

No matter how bad the success of the humeral IO was, the IV success was even worse – less than 50% first attempt success.

Do IOs improve outcomes?

IOs may make it less likely that compressions will be interrupted, but we cannot tell from this study.

IOs may make it more likely that potentially harmful medications will be given.

The most interesting numbers I saw were the total fluid infused – twice as much in the IV group as in either IO group. No explanation is given, other than the possible slower flow rate for an IO. This may help to prevent fluid overload for those patients not in need of having an IV line accidentally left wide open.

There is no evidence that IOs, IVs, tubes, or medications improve survival to discharge with a working brain.

ACLS drug therapy during CPR is often associated with increased rates of ROSC and hospital admission but not increased rates of long-term survival with good neurologic outcome.^[2]

Will this make the Three Stooges Pit Crew concept less of a comedy of errors to implement?

Probably not, but we can hope that the AHA does the right thing and eliminates all of the treatments that don’t work – ventilation, intubation, IV access, IO access, epinephrine, amiodarone, lidocaine, ~~atropine~~ – wait, they actually did remove atropine, so there is hope.

Footnotes:

^[1] Intraosseous Versus Intravenous Vascular Access During Out-of-Hospital Cardiac Arrest: A Randomized Controlled Trial.
Reades R, Studnek JR, Vandeventer S, Garrett J.
Ann Emerg Med. 2011 Dec;58(6):509-16.
PMID: 21856044 [PubMed - in process]

^[2] Medications for Arrest Rhythms
Part 8: Adult Advanced Cardiovascular Life Support
2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
Part 8.2: Management of Cardiac Arrest
Free Full Text Article with links to Free Full Text PDF download

Filed Under: AHA Guidelines, Cardiology, Heresy, Pharmacology, Rogue Medic

Does Epinephrine Improve Survival from Cardiac Arrest

12/12/2011 by Rogue Medic 1 Comment

Also posted over at Rogue Medic (now at EMS Blogs).

Even though epinephrine (adrenaline) is used automatically in cardiac arrest, and there is evidence that epinephrine helps to produce a pulse (ROSC – Return Of Spontaneous Circulation), there is no evidence that epinephrine improves the only survival statistic that matters – discharge from the hospital with a brain that still works. There were so many deviations from assignment protocol in their 2009 study,^[1] that the authors decided to examine the results based on what treatment patients actually received. They refer to epinephrine as adrenaline, which is the same drug. I will use adrenaline for consistency.

Our randomized study was analyzed on an intention-to-treat basis.⁴ As expected; some patients in the intravenous group had achieved ROSC before adrenaline could be given, while some in the no-intravenous group received adrenaline for different reasons. For example, it was permitted to place the IV line 5 min after ROSC. If re-arrest occurred, adrenaline could be administered if indicated by the CPR guidelines.⁷ ^[2]

In the no andrenaline group, 37 of the 433 patients did receive andrenaline.

In the adrenaline group, 85 of the 418 patients did not receive andrenaline.

For 3 patients, the authors were unable to tell whether andrenaline was given and these patients were excluded.

This changes the data to 367 patients in the adrenaline group and 481 patients in the no adrenaline group.

Patients in the adrenaline group were more likely to be admitted to hospital and an intensive care unit compared to the no-adrenaline group (OR 2.5 CI 1.9, 3.4 and OR 1.4 CI 1.0, 1.9, respectively). ^[2]

This is nothing new. Patients receiving andrenaline are more likely to have ROSC. All that really matters is what happens after ROSC.

If the patient loses pulses after ROSC, giving more adrenaline may not produce the desired effect – another ROSC.

First look at Table 1. The duration of CPR is much longer with the adrenaline group. Is this because of patients losing pulses?

Click on images to make them larger.

You can also see how few drugs were given to the no adrenaline group. They were not supposed to receive any drugs, but the use of adrenaline was the only criterion for reassigning patients in this reanalysis of the data. Atropine was given to 2% of the no adrenaline group and amiodarone was given to 2%. Was there overlap of these patients? We can’t tell.

The defibrillations were also significantly different. More patients were shocked in the adrenaline group, but more patients in the adrenaline group were in VF (Ventricular Fibrillation) initially. How many of the patients with PEA (Pulseless Electrical Activity) or Asystole developed VF after adrenaline? More shocks were also used for each patient. Was this due to rearrest?

Now looking at Table 2

Adrenaline starts out 2 1/2 times more likely to produce a pulse (ROSC), but a lot of those patients appear to have lost those pulses before admission to the hospital, since Table 2 shows that 69 of the 175 adrenaline patients admitted with CPR (CardioPulmonary Circulation) in progress. Adrenaline wears off in several minutes and produces a lot of undesirable side effects.

More is not better, especially since the doses of adrenaline being given are already many times larger than would be given to any living human.

Most important is the neurological function. I do not want to be resuscitated with only enough neurological function to spend the rest of my life watching reality TV in a long term care facility, or worse. That is not a successful resuscitation.

Adrenaline = 48% admitted to the hospital, but only 6% alive one year later.

No adrenaline = 27% admitted to the hospital, but 12% alive one year later.

Adrenaline (epinephrine) is not just changing the location of death, but is cutting overall survival in half.

Is getting pulses back a good enough reason to kill half of the patients who could survive?

Of the patients admitted to the hospital, 11% of the adrenaline group were discharged with good brain function.

Of the patients admitted to the hospital, 45% of the no adrenaline group were discharged with good brain function.

Of the patients admitted to the hospital, 12% of the adrenaline group were alive one year later.

Of the patients admitted to the hospital, 44% of the no adrenaline group were alive one year later.

The actual use of adrenaline may be a surrogate marker for patients with bad prognosis, but that has previously only been published from studies without a group randomized to not receiving drugs.²¹ ^[2]

There are many limitations of this study, but the authors do not pretend that this is the final answer on adrenaline (epinephrine) in cardiac arrest. They do point out that we are not providing good care by continuing to use adrenaline without studying the outcome that matters – survival with good neurological function.

5% of the no adrenaline group survivors had significant brain damage.

20% of the adrenaline group survivors had significant brain damage.

Maybe the good news is that adrenaline does not produce a lot of survivors.

Droperidol, QT prolongation, and sudden death – what is the evidence – Part I

12/01/2011 by Rogue Medic 1 Comment

Also posted over at Rogue Medic (now at EMS Blogs).

I am continuing to look for evidence that droperidol deserves to be given a ~~scarlet letter~~ black box warning. The authors of this literature review take a look at several articles and some case studies.

Because the outcome of interest, sudden death caused by torsades de pointes, is uncommon and difficult to assess, QT prolongation has become a surrogate marker for potential arrhythmogenicity and is therefore commonly used in research and by regulatory agencies.¹⁸^[1]

Surrogate endpoints are great for making it seem that we know more than we actually do know. When there is not enough information, surrogate end points are a way of saying, If this belief is true, and this other belief is also true, then Treatment Z is safe (or dangerous), or saves X number of lives per year (or kills X number of patients who otherwise would have been expected to live).

The example that I repeatedly use is the Cardiac Arrhythmia Suppression Trial,^[2] which ended up demonstrating that treatment based on the surrogate endpoint of eliminating PVCs (Premature Ventricular Contractions) because they are associated with a higher rate of death actually resulted in tens of thousands of extra deaths.^[3] That is the difference between looking at surrogate endpoints (making assumptions about death rates) and looking at actual death rates.

a consistent relationship between the length of the QT interval and the risk of torsades de pointes or sudden death is not clearly established and might vary from drug to drug and from individual to individual. Hundreds of drugs are known to prolong the QT interval, with widely variable degrees of evidence for clinical dysrhythmias.^16,17 ^[1]

What did the authors find?

Because of the small number of studies and articles identified, we were unable to perform a true systematic review (ie, meta-analysis)²² ^[1]

First, what does the FDA (Food and Drug Administration) label recommend as the dosage of droperidol?

Adult Dosage: The maximum recommended initial dose of droperidol is 2.5 mg I.M. or slow I.V. Additional 1.25 mg doses of droperidol may be administered to achieve the desired effect. However, additional doses should be administered with caution, and only if the potential benefit outweighs the potential risk.^[4]

As if that caution does not apply to the use of every medication.

In one surgical study of 40 patients receiving three weight-based doses of droperidaol, which if given to a 70 kg adult, would be doses of 7 mg, 12.25 mg, and 17.5 mg. Much higher than 2.5 mg. Yes, this is surgery, so what does the FDA recommend about surgical dosing?

Dosage should be individualized. Some of the factors to be considered in determining dose are age, body weight, physical status, underlying pathological condition, use of other drugs, the type of anesthesia to be used, and the surgical procedure involved.^[4]

They certainly were not excluding surgery from their dosing recommendation.

QTc interval prolongation occurred within 1 minute of injection and did not increase with time. Prolongation of the median QTc interval occurred by 37, 44, and 59 ms, respectively, in a dose-dependent fashion; this was also statistically significant (P<.003). ^[1]

Of these patients receiving very high doses, how many died?

No dysrhythmias developed. ^[1]

There was a lower dose surgical study and a long-term psychiatric study. Again, there was QT prolongation, but no arrhythmia (dysrhythmia and arrhythmia are synonyms).

And there is one ED (Emergency Department) retrospective study –

Over a 4-year period, 15,374 patients received 18,020 doses of droperidol. Of the 682 patients who had an ECG performed after droperidol administration, 14 (3.1%) had prolonged QT intervals (defined as >480 ms) without evidence of any bundle branch block. Four of the 14 patients had previously documented prolonged QT intervals not associated with droperidol use. A control group (n=100) who had ECGs performed without the administration of droperidol had a similar incidence of prolonged QT intervals (4.0%). ^[1]

The patients who received droperidol appear to have been less likely to develop QT segment prolongation. With droperidol – 3.1% had QT prolongation. Without droperidol – 4.0% had QT prolongation.

The control group only had 100 patients, so each patient represents 1.0%, but if droperidol is so dangerous there should be more QT prolongation in the droperidol group. Maybe there is something about the way that droperidol is used in the ED that decreases the supposed danger.

These studies do not mean that droperidol is safe, but they do raise questions about the rush to add a black box warning to the droperidol label.

With the black box warning, the FDA essentially says, Lawyers, look here. You don’t have to demonstrate that droperidol is dangerous – we did that for you. Go sue some doctors.

These studies do not support the claim by the FDA that droperidol is dangerous. In Part II, I will continue with the case studies reviewed by the authors.

Footnotes:

^[1] Droperidol, QT prolongation, and sudden death: what is the evidence?
Kao LW, Kirk MA, Evers SJ, Rosenfeld SH.
Ann Emerg Med. 2003 Apr;41(4):546-58. Review.
PMID: 12658255 [PubMed - indexed for MEDLINE]

^[2] Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial.
Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, Arensberg D, Baker A, Friedman L, Greene HL, et al.
N Engl J Med. 1991 Mar 21;324(12):781-8.
PMID: 1900101 [PubMed - indexed for MEDLINE]

Free Full Text Article from N Engl J Med with links to Free Full Text PDF download

CONCLUSIONS. There was an excess of deaths due to arrhythmia and deaths due to shock after acute recurrent myocardial infarction in patients treated with encainide or flecainide. Nonlethal events, however, were equally distributed between the active-drug and placebo groups. The mechanisms underlying the excess mortality during treatment with encainide or flecainide remain unknown.

^[3] C A S T and Narrative Fallacy
Rogue Medic
Article

^[4] DROPERIDOL injection, solution
[Hospira, Inc.]
FDA label
DailyMed
Dosage and administration

Filed Under: Cardiology, Heresy, Medical Mythology, Pharmacology, Research, Rogue Medic

Does RSI Protect Against Aspiration of Stomach Contents

Intramuscular Midazolam for Seizures – Part VI

Intramuscular Midazolam for Seizures – Part V

Intramuscular Midazolam for Seizures – Part IV

Intramuscular Midazolam for Seizures – Part III

Intramuscular Midazolam for Seizures – Part II

Nifekalant versus lidocaine for in-hospital shock-resistant ventricular fibrillation or tachycardia

Intraosseous Versus Intravenous Vascular Access During Out-of- Hospital Cardiac Arrest – A Randomized Controlled Trial

Does Epinephrine Improve Survival from Cardiac Arrest

Droperidol, QT prolongation, and sudden death – what is the evidence – Part I

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